Viral Hepatitis

The introduction of PEG-interferon for the treatment of hepatitis C infection clearly represents a major advance in the field and has increased the likelihood of achieving a sustained viral response.

For the first time, over 50% of all treated patients may clear the virus permanently after a 12-month course of PEG-interferon and ribavirin. As with any new therapy, familiarity with the product is needed to maximize efficacy. There are three main issues that should be addressed regarding the use of PEG-interferons: 1) who to treat, 2) how to dose and 3) how to make sure patients stay on therapy to maximize efficacy.

Who Should Be Treated with PEG-Interferon?

It is clear that PEG-interferon in combination with ribavirin is currently the standard of care for treatment-naive hepatitis C patients; no other therapy can achieve the rates of sustained viral response seen with this combination. Some patients who were prior non-responders to therapy may benefit from retreatment with PEG-interferon plus ribavirin. Those patients previously non-responding to interferon monotherapy are ideal candidates for retreatment with combination PEG-interferon plus ribavirin -- a significant percentage will achieve a sustained response.

A more difficult group of patients are those who did not achieve a sustained response to combination interferon alfa-2b and ribavirin therapy (Rebetron). Clinical trials are currently in progress to assess response in this group of patients. While we have no solid clinical data, some educated predictions can be made in terms of the likelihood of response. Those patients who lost virus while on Rebetron but then relapsed are the ones most likely to benefit from retreatment with PEG-interferon and ribavirin -- a significant percentage are likely to achieve a sustained response. Those that had a partial response to Rebetron (decrease in viral load >2 log) may also benefit from retreatment with PEG-interferon and ribavirin. The patients least likely to respond to retreatment are those who had no appreciable response to Rebetron. Patients who had no response to Rebetron and who had mild disease on liver biopsy may opt to wait for newer non-interferon-based therapies that may become available in the future. In contrast, those with significant fibrosis may want to undergo treatment with pegylated interferon and ribavirin as histologic improvement may occur even if the virus is not eradicated.

Another practical question is whether we should switch patients currently on Rebetron to combination pegylated interferon and ribavirin. The answer depends on how patients are responding to current therapy. Those who are still viremic, despite therapy with Rebetron are likely to benefit from switching to PEG-interferon plus ribavirin, a more potent combination. Among those who have had a response to Rebetron, switching to PEG-interferon plus ribavirin may be beneficial if >3 months of therapy remain. The convenience of once-a-week injections and possibly better quality of life with PEG-interferon therapy compared with regular interferon may entice many patients currently on Rebetron to switch to PEG-interferon plus ribavirin therapy.

How Should PEG-Interferon Be Dosed?

PEG-interferon alfa-2b (PEG-Intron) is dosed according to the patient's weight, at a dose of 1.5 micrograms per kilogram per week. To facilitate dosing in clinical practice, PEG-Intron is available in 4 different vial sizes: 50, 80, 120 and 150 micrograms per 0.5cc. The patient's weight will determine the vial size to use and the amount of medication that the patient should inject weekly. A dosing chart similar to the one shown below facilitates the prescribing process:

PEG-Interferon alfa-2b

Weightlb (kg)

Vial Size(µg/0.5ml)

Volume to Inject(ml/week)

Ribavirin Dose

<88 (<40)

50

0.5

800

88-111 (40-50)

112-141 (51-64)

80

0.4

0.5

800

142-166 (65-75)

167-187 (75-85)

120

0.4

0.5

1,000

188-231 (86-105)

>231 (>105)

150

0.5

1,200

1,400

For example, a patient who weighs 170 pounds would use a 120µg/0.5ml vial, and inject 0.5 cc per week. The weight-adjusted ribavirin dose recommended for this patient would be 1,000mg per day.

In contrast, PEG-interferon alfa-2a (Pegasys) is prescribed as a fixed dose of 180µg per week for all patients, regardless of weight. Currently, Pegasys is not FDA-approved for the treatment of hepatitis C; however approval is expected in the near future.

The timing of the interferon injection is also important. Most side effects will occur in the first 24 to 36 hours after injection. Thus, the patient should administer the medication on the day before they expect to be off from work; for most patients this means injecting the interferon on a Friday evening. Premedication with acetaminophen or ibuprofen greatly reduces the flu-like side effects that often accompany the injections.

The timing of ribavirin dosing is also important. It has become evident that taking the ribavirin with meals not only decreases the gastrointestinal side effects of ribavirin, but also increases the area under the curve of ribavirin blood levels; this translates into improved efficacy.

A final question about the use of PEG-interferon is how long should patients be treated. In general, the decision point regarding length of therapy is reached at the 6th month. For patients who are virus-negative at 6 months, completion of 12 months of therapy is recommended. For those who are virus-positive, the likelihood of viral clearance with continued therapy is very small. However, if the patient is still virus-positive at 6 months, but has achieved a marked reduction in viral load, continuation of therapy may result in viral clearance. It is not known if genotype 2 or 3 patients benefit from 12 months of therapy compared with 6 months. Unfortunately, all the trials were designed using 12 months of therapy, so this question remains unanswered and duration of therapy in genotype 2 or 3 patients should be individualized.

How to Make Sure Patients Stay on Therapy

Retrospective analysis of clinical data clearly shows that viral clearance is related to the amount of medication taken by the patient. The more dose reduction and dose interruption, the less likely the patient will respond. As a result, it is important to manage the side effects of therapy aggressively and minimize dose reductions and dose interruptions.

The side effect profile of PEG-interferon is similar to regular interferon; however quality of life studies suggest that patients have a better quality of life when treated with PEG-interferon compared to regular interferon. Some studies suggest that the side effect profile of pegylated interferon alfa-2a (Pegasys) in combination with ribavirin is less than that of regular interferon alfa-2b + ribavirin (Rebetron). It is important to note that there are no "unique" side effects to pegylated interferon.

The gastrointestinal side effects can be managed with frequent small meals and non-sedating antiemetics such as ondansetron or metoclopramide. In some patients acid suppression may help in controlling nausea. Caloric supplements are useful in patients with significant weight loss due to gastrointestinal side effects and loperamide can be used to control diarrhea.

Neutropenia can be severe and needs to be monitored closely. Dose reduction should be based on absolute neutrophil count and not on total white blood cell count. Patients with <750 neutrophils/mm3 should have dose reduction; those with <500 neutrophils/mm3 should have the treatment interrupted while the neutrophil count recovers. The use of G-CSF allows many patients to resume the prescribed dose of PEG-interferon by correcting neutropenia. Neutropenia tends to become evident during the first 8 weeks of therapy and it is recommended that patients be monitored using complete blood counts every other week for the first two months.

Neuropsychiatric side effects are not more common with PEG-interferon than with regular interferon, but continue to be the most common single cause for discontinuation of therapy. For this reason, aggressive management of neuropsychiatric side effects is essential. Depression, insomnia, irritability and anxiety are the most common side effects. Depression is best treated with selective serotonin reuptake inhibitors (SSRI). Which SSRI to use is debatable; there are no controlled randomized trials favoring one over the other. Many experts select a particular SSRI based on the symptoms associated with depression. For patients who have depression together with cognitive and behavioral slowing, flextime and venlafaxin are preferred. For those with depression and anger or anxiety, paroxetine is recommended. Sertaline provides a safe alternative for patients with advanced liver disease.

It is important to be particularly aggressive in treating depression. Patients should be screened and pre-treated for depression if there is a prior history of mild depression. Those with significant depression or past history of suicidal ideation should not be treated unless they are under close psychiatric monitoring. Patients with psychosis, personality disorders and manic-depressive disorders are poor candidates for therapy.

Insomnia is an important cause of fatigue, irritability and depression. Lifestyle changes, including no caffeinated beverages, avoiding exercise in the evening and dosing SSRIs in the morning rather than at night, may be sufficient to control the problem. Pharmacologic therapy with newer, shorter acting agents such as zaleplon or zolpidem is recommended for those not responding to conservative measures.

Irritability and anxiety can be treated with paroxetine or mirtazapine if depression is also present. The use of anxiolytics may be helpful, but they have addictive potential. Olanzapine may be helpful in irritable patients who have an addictive personality.

In summary, PEG-interferon in combination with ribavirin has become the treatment of choice for hepatitis C infection. Weight-based dosing of PEG-interferon and ribavirin appears to maximize efficacy. To provide our patients with the maximum benefit of therapy, aggressive management of side effects to minimize dose reduction and interruptions is extremely important.

This article was provided by TheBodyPRO. It is a part of the publication 66th Annual Scientific Meeting of the American College of Gastroenterology.

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